Reprogramming the pancreatic tumor microenvironment with immunotherapy

 描述（由申请人提供）：癌症免疫疗法是过去十年中最大的突破之一。然而，迄今为止，单药免疫疗法的成功仅限于少数实体恶性肿瘤，包括黑色素瘤、肾细胞癌和非小细胞肺癌。对检查点抑制剂有反应的癌症与胰腺导管腺癌 (PDA) 等没有反应的癌症之间的一个区别是肿瘤微环境 (TME) 的免疫状态。 PDA 与许多其他实体恶性肿瘤一样，被认为是“非免疫原性的”。我们最近报道，在单次新辅助剂量的粒细胞-巨噬细胞集落刺激因子（GM-CSF）分泌PDA疫苗（GVAX）后两周切除的PDA肿瘤诱导形成新型免疫活性三级淋巴聚集体，这是在未接种疫苗的患者切除的肿瘤组织中未观察到的有组织的淋巴结样结构。这项先前的研究首次表明，基于疫苗的免疫疗法可以将免疫静止的 TME 重新编程为免疫活跃的 TME。然而，PDA TME 中激活的 T 细胞会分泌干扰素-γ，从而上调 PD-1/PD-L1。因此，我们假设 GVAX 治疗可以启动 PDA TME 进行抗 PD-1/PD-L1 靶向治疗。我们的临床前研究支持了这一假设，表明抗 PD-1 或​​ PD-L1 抗体与疫苗相结合可提高效应 T 细胞浸润 PDA 的频率以及 PDA 荷瘤小鼠的治愈率。为了进一步检验这一假设，我们将招募 50 名可切除 PDA 的患者并随机参加一项 2 组临床试验，在手术切除 PDA 前两周接受一种单独使用 GVAX 加 Cytoxan (Cy) 或联合抗 PD-1 抗体 (nivolumab) 的新辅助治疗，然后接受五种额外的辅助免疫疗法。我们将比较治疗前核心活检的 PDA 标本和手术切除的肿瘤，并评估该临床试验的主要终点（疫苗诱导的淋巴聚集体中的 IL17A 表达）和次要终点（安全性、无病生存期和总体生存期）。我们 将评估抗 PD-1 抗体阻断与 Cy/GVAX 组合对 PD-L1/PD-1 相关途径、疫苗诱导的免疫调节特征以及外周和肿瘤内抗原特异性 T 细胞反应的影响。预计结果将确定调节 PDA TME 中 PD-1/PD-L1 通路的作用，确定可补偿 PD-1 阻断的替代调节通路，并确定 PDA TME 内免疫反应的特征。如果组合治疗组表现出淋巴聚集体中 IL17A 表达增强和/或比单独使用 Cy/GVAX 更好的生存率，我们将在一项随机研究中将两个治疗组与护理标准进行比较，样本量足以估计临床疗效的改善。

 DESCRIPTION (provided by applicant): Cancer immunotherapy is among the biggest breakthroughs in the last decade. However, the success of single agent immunotherapy has so far been limited to a few solid malignancies, including melanoma, renal cell carcinoma, and non-small cell lung cancer. One difference between cancers that have responded to checkpoint inhibitors and cancers like pancreatic ductal adenocarcinoma (PDA) that have not is the immune status of the tumor microenvironment (TME). PDA, like many other solid malignancies, was considered to be "non-immunogenic". We recently reported that PDA tumors resected just two weeks following a single neoadjuvant dose of a granulocyte-macrophage colony stimulating factor (GM-CSF) secreting PDA vaccine (GVAX) induces the formation of novel immunologically active tertiary lymphoid aggregates, organized lymph node-like structures that are not observed in tumor tissue resected from unvaccinated patients. This prior study showed for the first time that a vaccine-based immunotherapy can reprogram an immunologically quiescent TME into an immunologically active TME. However, activated T cells in the PDA TME secrete interferon-γ, which in turn upregulates PD-1/PD-L1. Thus, we hypothesize that treatment with GVAX primes the PDA TME for anti-PD-1/PD-L1-targeted therapy. Supporting this hypothesis, our preclinical studies showed that combining anti-PD-1 or PD-L1 antibodies with vaccines enhances the frequency of effector T cells infiltrating PDAs and the cure rate in PDA tumor-bearing mice. To further test this hypothesis, we will enroll and randomize 50 patients with resectable PDAs to a 2-arm clinical trial to receive either one neoadjuvant treatment with GVAX plus Cytoxan (Cy) alone or in combination with an anti-PD-1 antibody (nivolumab) two weeks prior to surgical resection of their PDAs, followed by five additional adjuvant immunotherapies. We will compare PDA specimens from a pre-treatment core biopsy and the surgically resected tumors and evaluate primary endpoint (IL17A expression in vaccine-induced lymphoid aggregates) and secondary endpoints (safety, disease free survival and overall survival) of this clinical trial. We will assess the effects of anti-PD-1 antibody blockade in combination with Cy/GVAX on the PD-L1/PD-1 associated pathways, vaccine-induced immune regulatory signatures, and peripheral and intratumoral antigen specific T cell responses. The results are expected to determine the role of modulating the PD-1/PD-L1 pathway in the PDA TME, to identify alternate regulatory pathways that may compensate for PD-1 blockade, and to identify signatures of immune response within the PDA TME. If the combinatorial treatment arm demonstrates enhanced IL17A expression in lymphoid aggregates and/or better survival than Cy/GVAX alone, we will compare the two treatment arms against standard of care in a randomized study with a sample size adequate to estimate an improvement in clinical efficacy.